MO045THE APPLICATION OF A NGS KIDNEY PANEL REVEALED KEY CHALLENGES OF PKD1-2 ANALYSIS: INTERPRETATION OF MISSENSE VARIANTS, SIGNIFICANCE OF VARIANTS IN DUPLICATED REGIONS AND HIGH ALLELIC HETEROGENEITY

Background and Aims Genetic testing has changed the clinical management of inherited kidney diseases patients, improving prognosis, surveillance and therapy. On the other hand, it has put geneticists and clinicians in front of new challenges, as the heterogeneity of these disorders and the high number of variants, with no clear genotype-phenotype correlation. Method 108 patients underwent genetic analysis through a kidney focused NGS panel, named Nephroplex, containing 119 genetic loci associated with inherited kidney disorders. The study aimed to addressed the genetic landscape of cystic individuals and to analyze PKD1 and PKD2 variants in non-cystic individuals. Results Following diagnostic criteria, patients were divided as cystic kidney diseases (n=36) and non-cystic kidney diseases (n=72). Among the group of cystic patients, a causative mutation was detected in 51% of cases. We found thirty-seven PKD1 and PKD2 variants in 26 out of 35 individuals. In particular, 12 variants were shown to be damaging and nine of that were reported in public database, as CLINVAR and Mayo Clinic databases. Among pathogenic variants, twelve were truncating and the remaining were missense variants. Of note, 7 out of 12 damaging PKD1 mutations were located in duplicated regions. Moreover, in three cystic patients, we found a (i) a frameshift hemizygote OFD1 mutation (ii) compound heterozygote PKHD1 variants and (iii) a frameshift MUC1 variant, framing the diagnosis of oro-facio-digital type 1, autosomal recessive polycystic kidney disease and autosomal dominant tubulointerstitial disease, respectively. Interestingly, we detected 28 PKD1-2 rare variants in 21 out of 75 adult non cystic patients (28%). The most were observed in PKD1 genes (82% vs 18% in PKD2). Eighteen of 28 variants were described in the literature as likely benign or as mutations of uncertain significance, while we found 10 novel variants. In silico analysis revealed as pathogenic a frameshift mutation located in exon 15. Of note, the great part of these variations reside into the duplicated PKD1 regions. Conclusion Our data showed that genetic analysis of ADPKD retains unique challenges, given the high degree of homology of PKD1 with his pseudogenes and the high allelic heterogeneity in non-cystic individuals.